Dickkopf-3 Acts as a Modulator of B Cell Fate and Function
Dickkopf-3 Acts as a Modulator of B Cell Fate and Function
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DOI：
10.4049/jimmunol.1402160
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发表时间：
2015-03-15
影响因子：
4.4
通讯作者：
Arnold, Bernd
中科院分区：
文献类型：
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作者：
Ludwig, Julia;Federico, Giuseppina;Arnold, Bernd
负责产生成熟的B1和B2细胞区室的机制仍然知之甚少。在这项研究中，我们证明了Dickkopf-3（DKK 3）的缺乏导致B细胞区室的组成发生变化，这是由于B细胞的发育和维持程序发生改变。在前和未成熟B细胞阶段，B2细胞的发育受损，导致成年DKK 3缺陷小鼠中滤泡B细胞数量减少。此外，DKK 3通过降低B1细胞的存活和增殖行为来限制B1细胞在外周的自我维持。DKK 3可能通过BCR信号传导途径起作用，因为BCR刺激后的Ca 2+内流增加，并且在不存在DKK 3的情况下，SiglecG（一种显示出抑制钙信号传导的分子）下调。DKK 3缺陷小鼠表现出改变的Ab反应和细胞因子IL-10的分泌增加。此外，DKK 3在系统性红斑狼疮模型中限制自身免疫。总之，我们将DKK 3鉴定为干扰B细胞命运以及B细胞维持程序的新型调节剂，导致B细胞免疫应答的变化。
The mechanisms responsible for the generation of a mature B1 and B2 cell compartment are still poorly understood. In this study, we demonstrated that absence of Dickkopf-3 (DKK3) led to changes in the composition of the B cell compartment, which were due to an altered development and maintenance program of B cells. Development of B2 cells was impaired at the pre- and immature B cell stage, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice. Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation behavior of B1 cells. DKK3 may act via the BCR signaling pathway, as Ca2+ influx upon BCR stimulation was increased and SiglecG, a molecule shown to inhibit Calcium signaling, was downregulated in the absence of DKK3. DKK3-deficient mice exhibited altered Ab responses and an increased secretion of the cytokine IL-10. Additionally, DKK3 limited autoimmunity in a model of systemic lupus erythematosus. In summary, we identified DKK3 as a novel modulator interfering with B cell fate as well as the maintenance program of B cells, leading to changes in B cell immune responses.